The vitamin A metabolite all-trans-retinoic acid (RA) and its natural and synthetic derivatives (retinoids) exert a broad range of biological effects.sup.1,2. Clinically, retinoids are important therapeutics in the treatment of skin diseases and cancers.sup.3-6. Understanding how the multitude of retinoid actions can be mediated at the molecular level has been greatly enhanced by the cloning and characterization of specific nuclear receptors, the retinoic acid receptors (RARs).sup.7-12 and the retinoid X receptors (RXRs).sup.13-17. RARs and RXRs are part of the steroid/thyroid hormone receptor superfamily.sup.18,9. Both types of receptors are encoded by three distinct genes, .alpha., .beta., and .gamma., from which, in the case of RARs, multiple isoforms can be generated.sup.20-22. Interestingly, while RARs are specific to vertebrates, the RXRs have been well conserved from Drosophila to man.sup.17,23. Despite the considerable advances in the understanding of the molecular mechanisms of retinoid receptor action in recent years, a central question of whether distinct molecular pathways for naturally occurring retinoids exist has not yet been answered. The recent observation that the RA stereoisomer 9-cis-RA binds with high affinity to RXRs.sup.23,24 suggested a retinoid response pathway distinct from that of all-trans-RA. However, it was almost simultaneously discovered by several laboratories that RARs require interaction with auxiliary receptors for effective DNA binding and function and that RXRs are such auxiliary receptors.sup.15,16,26-29. Hence, RARs appear to function effectively only as heterodimeric RAR/RXR complexes, or in combination with comparable auxiliary proteins that still need to be identified. Similarly, RXRs were shown to require RARs, thyroid hormone receptors (TRs), or Vitamin D.sub.3 receptors (VDRs) for effective DNA binding.sup.15,16,26-29. Thus, from these DNA binding studies, RXRs appeared to be able to function predominantly if not exclusively as auxiliary receptors, thereby playing a crucial role in generating a high degree of diversity and specificity of transcriptional controls and mediating the highly pleiotropic effects of different hormones by increasing DNA affinity and specificity for at least 3 different classes of ligand-activated receptors.
Contrary to these findings, the present invention provides that RXRs form homodimers. The invention provides that these homodimers effectively bind to specific response elements in the absence of auxiliary receptors and their DNA binding specificity is distinct from that of the RXR containing heterodimers. The invention demonstrates a novel mechanism for retinoid action by which a ligand induced-homodimer mediates a distinct retinoid response pathway. Additionally, ligands are provided which selectively activate RXR homodimer formation.